As part of a systematic comparison of substrate-selective monoamine oxidase (MAO)-inhibiting antidepressants, a dose-response study of deprenyl was completed this year. Minimal antidepressant effects were obtained at an MAO-B selective deprenyl dose of 10 mg/day, which inhibited platelet MAO activity greater than 95%. With higher doses (30 and 60 mg/day), reductions in plasma MHPG approached those found with non-selective inhibitors or the MAO-A selective inhibitor, clorgyline. Moreover, a markedly increased pressor sensitivity to intravenous tyramine occurred with the higher deprenyl doses. These results add further support to our hypotheses that both antidepressant activity and the potentiation of tyramine sensitivity are most closely linked with MAO-A inhibition and changes in noradrenergic functions. In animal studies of two new MAO-A selective reversible inhibitors, cimoxatone most closely resembled clorgyline in its effects on monoamine metabolism, while amiflamine had relatively greater effects on serotonin metabolism than did clorgyline or cimoxatone. Amiflamine, however, also possessed monoamine-releasing effects, complicating its use in studying the consequences of selective MAO-A inhibition.